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Schulte-Merker et al. 1994 ). Conversely, endogenous Fgf signals are not able to
induce mesoderm in embryos expressing a truncated Activin receptor (Hemmati-
Brivanlou et al. 1992 ). Finally, vegetal explants adopt mesodermal fates in the pres-
ence of exogenously added bFgf/Fgf2 and endogenous Activin-like signals (Cornell
et al. 1995 ). This indicates that in the frog, Fgf signals act as a competence factor that
directs cells to adopt mesodermal fates instead of endoderm in response to TGF-β
signals. The Fgf and Activin pathways act in parallel, at least initially, since Fgf
ligands and Activin are both expressed maternally. Crosstalk between the two path-
ways may be mediated at the level of their transcriptional effectors. p53 is required
for the expression of mesodermal markers in Xenopus, and induces mesoderm when
overexpressed in animal caps (Cordenonsi et al. 2003 , 2007 ). Activation of the RTK/
Ras pathway results in an N-terminal phosphorylation of p53. This form of p53 binds
to Smad2 and forms a complex that activates TGF-β responsive target genes in pre-
sumptive mesodermal cells. Expression of fgf3 and fgf8 depends upon the maternally
provided transcription factor, VegT, and Fgf expression can be rescued in VegT
depleted embryos by expression of xnr2 (Fig. 7.9a) (Kofron et al. 1999 ).
In zebrafish, Fgf signaling is required for Nodal signals to induce mesoderm, but
not to induce endoderm (Rodaway et al. 1999 ; Mathieu et al. 2004 ). Nodal signals
induce expression of fgf3 and fgf8 in the presumptive mesendoderm (Mathieu et al.
2004 ). Activation of Fgf inhibits expression of the endodermal marker casanova
(cas), whereas cas expression is expanded when Fgf signaling is blocked (Mizoguchi
et al. 2006 ). Thus in zebrafish, Fgf signals act downstream of Nodal signals to con-
trol the balance between mesoderm and endoderm. In addition, Fgf8 or Fgf3 can
induce expression of components of the Nodal signal transduction pathway to main-
tain mesodermal identity (Mathieu et al. 2004 ). This indicates that Fgf and Nodal
signals participate in a positive feedback loop that amplifies expression of both
mesoderm-inducing signals (Fig. 7.9b).
7.7.2 Control of Nodal-Related Gene Expression
7.7.2.1 Mouse
There is strong evidence that nodal gene expression is maintained by positive feed-
back loop in all vertebrates. In the mouse, expression of a nodal-reporter gene in the
epiblast depends upon the function of a conserved Activin/Nodal response element
in the first intron (Brennan et al. 2001 ; Norris et al. 2002 ). Nodal expression is
induced in the proximal region of the epiblast by unknown signals emanating from
the extraembryonic ectoderm (ExE). Nodal expression rapidly spreads throughout
the entire epiblast and eventually in the VE, where it is required for primitive streak
formation in the epiblast (Fig. 7.10a) (Varlet et al. 1997 ). Several experiments indi-
cate that nodal expression in the epiblast and the VE depends on a positive feedback
loop. First, nodal expression is expanded in embryos lacking the Nodal antagonist,
Antivin/Lefty2, resulting in an expansion of mesoderm (Meno et al. 1999 ). Secondly,
W. Tseng et al.